Rapid PROTAC discovery platform: nanomole scale array synthesis and direct screening of reaction mixtures to facilitate the expedited discovery and follow-up of PROTAC hits. DOI Creative Commons
Mateusz P. Plesniak,

Emilia K. Taylor,

Frederik Eisele

и другие.

Опубликована: Июль 18, 2023

Precise linker length, shape and attachment point are all integral components to designing efficacious PROTACs. Due the increased synthetic complexity of these heterobifunctional degraders difficulty computational modelling aid PROTAC design, exploration structure-activity-relationship (SAR) remains mostly empirical, which requires a significant time resource investment. To facilitate rapid hit finding we developed capabilities for parallel synthesis purification by harnessing an array pre-formed E3-ligand intermediates. In next iteration this approach, rapid, nanomole-scale methodology using amide coupling that enables direct screening non-purified reaction mixtures in cell-based degradation assays, as well logD EPSA measurements. This approach greatly expands accelerates SAR (5 days instead several weeks) while nanomole amounts reagents. Lastly, it avoids laborious solvent-demanding mixtures, thus making economical more sustainable finding.

Язык: Английский

One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp2)–C(sp3) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis DOI

Christine Marie Arndt,

Jacqueline Bitai,

Jessica Brunner

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(24), С. 16939 - 16952

Опубликована: Дек. 14, 2023

In this study, a one-pot synthesis via photoinduced C(sp2)–C(sp3) coupling followed by amide formation to access proteolysis targeting chimeras (PROTACs) was developed. The described protocol studied on cereblon (CRBN)-based E3-ligase binders and (+)-JQ-1, bromodomain inhibitor, generate BET (bromodomain extra terminal domain) protein degraders. generated PROTACs were profiled in vitro tested for their degradation ability with several potent candidates identified. Upfront, the individual reactions of transformation carefully optimized CRBN binder functionalization multiple heterobifunctional linker moieties designed synthesized. Separate scopes detailing PROTAC are report as well library miniaturization study showing high-throughput compatibility. Overall, developed provides rapid single process, thereby allowing efficient generation CRBN-based libraries.

Язык: Английский

Процитировано

8
Rapid PROTAC discovery platform: nanomole scale array synthesis and direct screening of reaction mixtures to facilitate the expedited discovery and follow-up of PROTAC hits. DOI Creative Commons
Mateusz P. Plesniak,

Emilia K. Taylor,

Frederik Eisele

и другие.

Опубликована: Июль 18, 2023

Precise linker length, shape and attachment point are all integral components to designing efficacious PROTACs. Due the increased synthetic complexity of these heterobifunctional degraders difficulty computational modelling aid PROTAC design, exploration structure-activity-relationship (SAR) remains mostly empirical, which requires a significant time resource investment. To facilitate rapid hit finding we developed capabilities for parallel synthesis purification by harnessing an array pre-formed E3-ligand intermediates. In next iteration this approach, rapid, nanomole-scale methodology using amide coupling that enables direct screening non-purified reaction mixtures in cell-based degradation assays, as well logD EPSA measurements. This approach greatly expands accelerates SAR (5 days instead several weeks) while nanomole amounts reagents. Lastly, it avoids laborious solvent-demanding mixtures, thus making economical more sustainable finding.

Язык: Английский

Процитировано

2